Epidermolysis bullosa is a rare inherited condition that causes the skin to blister. The skin of those with the disorder is so fragile that even minor rubbing can cause blistering.
A severe subtype of EB, called recessive dystrophic epidermolysis bullosa (RDEB), can occur in children who lack a protein called type 7 collagen, or COL7. Its hallmarks are the formation of painful blisters and wounds on the skin and the mucous membranes that cover body openings. Children with the condition have a shorter life expectancy due to infections, organ failure, and squamous cell carcinoma, the second most common skin cancer.
There is no cure for RDEB. The only treatments available are aimed at caring for wounds.
Researchers are working on developing a gene therapy approach to treat RDEB. It involves genetically modifying a patient’s own cells, then transplanting them back onto their skin.
What is COL7?
COL7 is a protein produced by skin cells called keratinocytes and fibroblasts. Although both types of cells can secrete COL7, scientists believe keratinocytes are responsible for secreting COL7 at the dermal–epidermal junction. That skin layer helps keep the upper epidermis attached to the dermis underneath. The junction’s role is to help support the epidermis and form a barrier that prevents an exchange of skin cells and large molecules.
COL7, which is composed of three alpha collagen chains, helps anchor two skin layers: the external epithelia and the underlying stroma. Mutations in the COL7A1 gene, which produces COL7 protein, are associated with RDEB. The mutations lead to the production of abnormal COL7 protein or abnormal skin anchoring assemblies known as fibrils. The result is that the epidermis and dermis are unable to stick to each other properly.
What is gene therapy?
Gene therapy involves delivering healthy copies of a gene to patients’ cells, where they can be used to make a normal protein.
The general approach to gene therapy for the treatment of RDEB is to obtain a sample of a person’s skin, then collect epidermal stem cells, transfer a functional COL7A1 gene into these cells using a harmless virus, grow the corrected cells in thin sheets in a laboratory, then graft the sheets back to wounds.
Gene therapy research in EB
Research has also shown that COL7A1 gene transfer in connective-tissue components known as fibroblasts can be successful in animals. For example, injecting genetically corrected fibroblasts into the dermis of mice with RDEB led to the fibroblasts secreting COL7 and forming skin anchoring assemblies.
Gene therapy in clinical trials for RDEB
A Phase 1/ 2 clinical trial (NCT01263379) is currently recruiting participants to test the potential of gene therapy in RDEB patients. A primary objective of the study will be to see whether the therapy produces COL7 protein and anchoring assemblies at weeks 4, 12, and 52. Researchers will also look at the frequency of adverse events during the 52 weeks.
Researchers hope to enroll 10 participants in the study, which is expected to be completed by December 2025.
Disadvantages of gene therapy in EB
Disadvantages of a gene therapy approach to treat EB are that it is an intensive procedure, and the corrected-cell grafts can be applied only to certain areas of the skin. As an example, they would be difficult to use at mucosal sites, or places where skin covers body openings such as the eyes and ears.
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